PROJECT SUMMARY Kaposi's sarcoma (KS) is one of the most common cancers in HIV-positive patients, and frequently occurs in the oral mucosa, skin, and lymph nodes due to KS Herpes Virus (KSHV) infection. Proliferating KS tumor cells are believed to originate from blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs), as KS cells express the signature genes of both cell types. LECs and BECs are closely related because LECs are derived from BECs during development, thus their gene expression profiles remain similar even after development. Despite their similarities, these two types of endothelial cells exhibit significant differences in their KSHV pathologies. One of the most recognized differences is that LECs are much more permissive to KSHV infection than BECs. Although this differential infectivity was first described more than a decade ago, neither rigorous follow-up characterization, nor elucidation of the underlying molecular basis, of this important lineage-specific phenotype are understood to date. In the current study, we propose to study the molecular underpinnings of the increased KSHV infectivity in LECs. We hypothesize that CEACAM1 and CEACAM6 proteins function as a novel KSHV receptor predominantly expressed in LECs, enabling the increased permissiveness of LECs. Accordingly, we will identify and characterize these CEACAMs (Aim1) and dissect the interactions between KSHV and these CEACAM proteins (Aim2). The outcome of this study will not only define the molecular basis of the enhanced permissiveness of LECs to KSHV infection, but also provide new knowledge on lymphatic-specific KSHV pathologies. In sum, this project will advance our current understanding of KSHV-host cell interactions, help broaden therapeutic options against KS, and offer important insight into the histogenetic origin of KS.